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1.
J Med Chem ; 64(8): 4857-4869, 2021 04 22.
Article in English | MEDLINE | ID: mdl-33821636

ABSTRACT

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.


Subject(s)
ATP-Dependent Proteases/antagonists & inhibitors , Drug Design , Mitochondrial Proteins/antagonists & inhibitors , Protease Inhibitors/chemistry , ATP-Dependent Proteases/metabolism , Binding Sites , Boronic Acids/chemistry , Boronic Acids/metabolism , Boronic Acids/pharmacology , Bortezomib/chemistry , Bortezomib/metabolism , Cell Line , Cell Survival/drug effects , Humans , Mitochondrial Proteins/metabolism , Molecular Docking Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Proteasome Endopeptidase Complex/chemistry , Proteasome Endopeptidase Complex/metabolism , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Structure-Activity Relationship
2.
Cancer Res ; 76(6): 1591-602, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26825170

ABSTRACT

Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/metabolism , Lung Neoplasms/drug therapy , Mutation/drug effects , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Female , Lung Neoplasms/metabolism , Mice , Mice, Nude , Phosphorylation/drug effects , Rats , Xenograft Model Antitumor Assays/methods
3.
Cancer Lett ; 274(2): 243-9, 2009 Feb 18.
Article in English | MEDLINE | ID: mdl-19008038

ABSTRACT

Oncogene addiction due to Myc deregulation has been identified in a variety of tumor types. In order to identify pharmacological agents that cause selective apoptosis in tumors with deregulated Myc expression, we designed a cell-based screening assay based on our Anti-cancer Screening Apoptosis Program (ASAP) technology targeting increased activity in a "Myc-addicted" cancer cell panel. We have identified a novel set of substituted 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones that activates apoptosis in cancer cell lines with deregulated Myc, but show low activity in cell lines where Myc is not deregulated. Apoptosis induced by these compounds is rapid, and is associated with a significant downregulation of Myc protein. Selective knockdown of Myc levels in these cells by RNA interference increased sensitivity to apoptosis with compound treatment. By targeting the Myc pathway in Myc-addicted cancer cells, we have identified a novel class of apoptotic inducers that selectively and efficiently target cancer cells with deregulated Myc.


Subject(s)
Apoptosis/drug effects , Genes, myc , Quinolones/pharmacology , Caspases/metabolism , Cell Cycle , Cell Line, Tumor , Down-Regulation , Enzyme Activation , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Polymerase Chain Reaction , RNA Interference , RNA, Small Interfering , Ubiquitination
4.
Cancer Gene Ther ; 12(8): 691-8, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15877084

ABSTRACT

Cultured primary human cells have been widely used to assess the selectivity of oncolytic viruses as potential anticancer agents. As culture conditions can potentially have a significant impact on virus replication and ultimately cell killing, we evaluated the effects of dl309, a wild-type adenovirus, and dl01 / 07, a conditionally replicating adenovirus mutant, on quiescent and proliferating primary mammary epithelial cells. When primary cells were induced into quiescence, both viruses exhibited similar attenuated cell killing. However, cell killing by dl309 was superior to dl01 / 07 in proliferating primary cells. Analysis of viral effects at the level of entry, E2F activation, DNA replication, and late gene expression indicated that attenuation of dl309 in quiescent cells correlated with decreased expression of viral late genes such as hexon. In contrast, attenuation of dl01 / 07 in quiescent cells correlated with inefficient induction of E2F activity and inability to undergo efficient DNA replication. In proliferating cells, dl309 replicated efficiently, whereas dl01 / 07 still showed attenuated replication. In summary, our results indicate the intrinsic preference of wild-type adenoviruses for killing proliferating cells, which is an attractive feature for using adenoviruses as oncolytic agents. These results also highlight the need for the use of appropriate growth conditions for primary cells in vitro to distinguish subtle differences in cell killing among various oncolytic viruses.


Subject(s)
Adenoviridae/physiology , Antineoplastic Agents/toxicity , Capsid Proteins/genetics , Virus Replication , Adenoviridae/genetics , Cells, Cultured , DNA, Viral/analysis , DNA, Viral/genetics , Epithelial Cells/chemistry , Epithelial Cells/metabolism , Gene Expression , Genes, Viral , Humans , Transduction, Genetic
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